Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/78—Ring systems having three or more relevant rings
  • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
  • C07D311/82—Xanthenes
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
  • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
  • C07D327/06—Six-membered rings
  • C07D327/08—[b,e]-condensed with two six-membered carbocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
  • C07D339/08—Six-membered rings

Definitions

• the present invention relates to compounds that inhibit matrix metalloproteinases and to methods of inhibiting matrix metalloproteinases using the compounds. More particularly, the present invention relates to a method of treating diseases in which matrix metalloproteinases are involved such as multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurysm, heart failure, periodontal disease, corneal ulceration, burns, decubital ulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, osteoporosis, rheumatoid or osteoarthritis, renal disease, left ventricular dilatation, or other autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes.
• diseases in which matrix metalloproteinases are involved such as multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurysm, heart failure, periodontal disease, corneal ulceration, burns, decubital ulcers, chronic ulcers or wounds, cancer met
• the compounds of the present invention are inhibitors of the matrix metalloproteinases, e.g., stromelysin-1 (MMP-3) and gelatinase A (72 kDa gelatinase) (MMP-2).
• MMP-3 matrix metalloproteinases
• MMP-2 gelatinase A (72 kDa gelatinase)
• Stromelysin-1 and gelatinase A are members of the matrix metalloproteinases (MMP) family. Other members include fibroblast collagenase (MMP-1), neutrophil collagenase, gelatinase B (92 kDa gelatinase) (MMP-9), stromelysin-2, stromelysin-3, matrilysin (MMP-7), collagenase 3 (MMP-1 3), and the newly discovered membrane-associated matrix metalloproteinases (Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M., Nature, 1994;370:61-65).
• MMP-1 matrix metalloproteinases
• the catalytic zinc in matrix metalloproteinases is typically the focal point for inhibitor design.
• the modification of substrates by introducing zinc chelating groups has generated potent inhibitors such as peptide hydroxamates and thiol-containing peptides.
• Peptide hydroxamates and the natural endogenous inhibitors of MMPs have been used successfully to treat animal models of cancer and inflammation.
• the ability of the matrix metalloproteinases to degrade various components of connective tissue makes them potential targets for controlling pathological processes.
• the rupture of atherosclerotic plaques is the most common event initiating coronary thrombosis.
• Destabilization and degradation of the extracellular matrix surrounding these plaques by MMPs has been proposed as a cause of plaque fissuring.
• the shoulders and regions of foam cell accumulation in human atherosclerotic plaques show locally increased expression of gelatinase B, stromelysin-1, and interstitial collagenase.
• In situ zymography of this tissue revealed increased gelatinolytic and caseinolytic activity (Galla Z. S., Sukhova G. K., Lark M.
• Inhibitors of matrix metalloproteinases will have utility in treating degenerative aortic disease associated with thinning of the medial aortic wall. Increased levels of the proteolytic activities of MMPs have been identified in patients with aortic aneurysms and aortic stenosis (Vine N. and Powell J. T., "Metalloproteinases in degenerative aortic diseases,” Clin. Sci., 1991;81:233-239).
• Heart failure arises from a variety of diverse etiologies, but a common characteristic is cardiac dilation which has been identified as an independent risk factor for mortality (Lee T. H., Hamilton M. A., Stevenson L. W., Moriguchi J. D., Fonarow G. C., Child J. S., Laks H., and Walden J. A., "Impact of left ventricular size on the survival in advanced heart failure," Am. J. Cardiol., 1993;72:672-676). This remodeling of the failing heart appears to involve the breakdown of extracellular matrix. Matrix metalloproteinases are increased in patients with both idiopathic and ischemic heart failure (Reddy H. K., Tyagi S. C., Tjaha I.
• CHF Congestive heart failure
• CHF cardiac function
• cardiac function especially contractile or pump function
• Heart failure is said to exist whenever the myocardial injury is of sufficient severity to reduce the heart's capacity to pump an adequate output of blood to satisfy the body's tissue requirements either at rest or during exercise.
• the disease state of heart failure is not a static situation, but instead progressively worsens until death occurs either suddenly (e.g., by cardiac arrhythmia or embolism to the brain or lung) or gradually from pump failure per se.
• the progressive decline in heart function in patients with CHF is characterized by progressive enlargement of the ventricular chambers (i.e., ventricular dilatation) and thinning and fibrosis of the ventricular muscle.
• the progressive ventricular enlargement and accompanying histologic changes in the ventricular muscle are termed "remodeling," a process that involves changes in myocardiocyte structure as well as changes in the amount and composition of the surrounding interstitial connective tissue.
• An important constituent of the interstitial connective tissue is a matrix of fibrillar collagen, the "tissue scaffolding" that contributes to the maintenance of proper ventricular geometry and structural alignment of adjoining cardiomyocytes.
• the interstitial collagen matrix is subject to increased dissolution and repair during "remodeling" that leads to ventricular enlargement and progressive heart failure.
• the deterioration of the collagen matrix is effected by increased activity of matrix metalloproteases, the inhibition of which is a new treatment for heart failure and ventricular dilatation.
• Ventricular dilatation the severity of which is measured by the end-diastolic and end-systolic volumes, is a prognostic marker of the probability of subsequent morbidity and mortality.
• the larger the ventricular chamber dimensions the greater the likelihood of subsequent morbid events.
• pump function impaired by remodeling and ventricular dilation but the enlarged chambers are prone to formation of clots, which can lead to stroke or embolism to other major organs (e.g., kidney, legs, intestinal tract).
• Standard treatment for heart failure utilizes diuretics to decrease fluid retention, angiotensin converting enzyme inhibitors (ACE-Is) to reduce cardiac workload on the failing heart via vasodilation, and in the final stages of failure the positive inotrope digitalis to maintain cardiac output.
• ACE-Is angiotensin converting enzyme inhibitors
• ACE-Is have the benefit of increasing longevity unlike diuretics or positive inotropes
• the beneficial effect of ACE-Is is limited to delaying death by only about 18 months.
• Clinical trials with ⁇ -adrenergic blockers were recently conducted based on the hypothesis that reducing sympathetic drive would decrease the metabolic load on heart muscle cells. Unfortunately, this class of compounds was also found to not have a substantial effect on the progression of heart failure. The failure or limited success of previous heart failure therapies clearly shows that the controlling mechanism(s) mediating heart failure has not been targeted.
• vascular smooth muscle cells vascular smooth muscle cells
• antisera capable of selectively neutralizing gelatinase A activity also inhibited VSMC migration across basement membrane barrier.
• gelatinase A activity increased more than 20-fold as VSMCs underwent the transition from a quiescent state to a proliferating, motile phenotype (Pauly R. R., Passaniti A., Bilato C., Monticone R., Cheng L., Papadopoulos N., Gluzband Y. A., Smith L., Weinstein C., Lakatta E., and Crow M. T., "Migration of cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular differentiation," Circulation Research, 1994;75:41-54).
• Deficiency or defects in any component of the filtration barrier may have catastrophic consequences for longer term renal function.
• hereditary nephritis of Alport's type associated with mutations in genes encoding ECM proteins, defects in collagen assembly lead to progressive renal failure associated with splitting of the GBM and eventual glomerular and interstitial fibrosis.
• inflammatory renal diseases such as glomerulonephritis
• cellular proliferation of components of the glomerulus often precede obvious ultrastructural alteration of the ECM matrix.
• Cytokines and growth factors implicated in proliferative glomerulonephritis such as interleukin-1, tumor necrosis factor, and transforming growth factor beta can upregulate metalloproteinase expression in renal mesangial cells (Martin J. et al., "Enhancement of glomerular mesangial cell neutral proteinase secretion by macrophages: role of interleukin 1," J. Immunol., 1986;137:525-529; Marti H. P. et al., "Homology cloning of rat 72 kDa type IV collagenase: Cytokine and second-messenger inducibility in mesangial cells," Biochem.
• MMP-2 rat mesangial cell MMP
• MMP-2 rat mesangial cell MMP
• cytokines Bosset P. D., Levy A. T., Margulies I., Liotta L. A., Stetler-Stevenson W. G., "Independent expression and cellular processing of Mr 72,000 type IV collagenase and interstitial collagenase in human tumorigenic cell lines," Cancer Res., 1990;50:6184-6191; Marti H. P.
• MMP-2 can specifically degrade surrounding ECM, it also affects the phenotype of adjacent mesangial cells. Inhibition of MMP-2 by antisense oligonucleotides or transfection techniques can induce a reversion of the proliferative phenotype of cultured mesangial cells to a quiescent or non-proliferative phenotype mimicking the natural in vitro behavior of these cells (Kitamura M.
• Collagenase and stromelysin activities have been demonstrated in fibroblasts isolated from inflamed gingiva (Uitto V. J., Applegren R., and Robinson P. J., "Collagenase and neutral metalloproteinase activity in extracts from inflamed human gingiva," J. Periodontal Res., 1981;16:417-424), and enzyme levels have been correlated to the severity of gum disease (Overall C. M., Wiebkin O. W., and Thonard J. C., "Demonstrations of tissue collagenase activity in vivo and its relationship to inflammation severity in human gingiva," J. Periodontal Res., 1987;22:81-88).
• Stromelysin is produced by basal keratinocytes in a variety of chronic ulcers (Saarialho-Kere U. K., Ulpu K., Pentland A. P., Birkedal-Hansen H., Parks W. C., Welgus H. G., "Distinct populations of basal keratinocytes express stromelysin-1 and stromelysin-2 in chronic wounds," J. Clin. Invest., 1994;94:79-88).
• Stromelysin-1 mRNA and protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of proliferating epidermis. Stromelysin-1 may thus prevent the epidermis from healing.
• Inhibitors of MMPs have shown activity in models of tumor angiogenesis (Taraboletti G., Garofalo A., Belotti D., Drudis T., Borsotti P., Scanziani E., Brown P. D., and Giavazzi R., Journal of the National Cancer Institute, 1995;87:293; and Benelli R., Adatia R., Ensoli B., Stetler-Stevenson W. G., Santi L., and Albini A., Oncology Research, 1994;6:251-257).
• TIMP-1 and TIMP-2 prevented the formation of collagen fragments, but not proteoglycan fragments, from the degradation of both the bovine nasal and pig articular cartilage models for arthritis, while a synthetic peptide hydroxamate could prevent the formation of both fragments (Andrews H. J., Plumpton T. A., Harper G. P., and Cawston T. E., Agents Actions, 1992;37:147-154; Ellis A. J., Curry V. A., Powell E. K., and Cawston T. E., Biochem. Biophys. Res. Commun., 1994;201:94-101).
• Leukocytic migration across the blood-brain barrier is known to be associated with the inflammatory response in EAE. Inhibition of the metalloproteinase gelatinase A would block the degradation of extracellular matrix by activated T-cells that is necessary for CNS penetration.
• WO 97/00675 discloses compounds of the formula: ##STR2## wherein B can be H and A can be --SO 2 R 1 , wherein R 1 is --NR 2 R 3 and R 2 can be H and R 3 is a group containing a carboxylic acid radical.
• the compounds are disclosed as agents for the treatment of pathologies in which the erosion of the cartilaginous and bone matrix occurs.
• EP 0 307 879 discloses compounds of the formula: ##STR3## wherein R 1 is a trihalomethyl, a carboxy moiety, or a sulfonamido, and X is alkyl, alkoxy, or halo. The compounds are disclosed as being inhibitors of the aldose reductase enzyme system.
• the present invention provides compounds of Formula I: ##STR4## and pharmaceutically acceptable salts thereof,
• X and Y are independently O, S(O) n , CH 2 , C ⁇ O, NH, or NC 1 -C 6 alkyl, provided that X and Y are not both ##STR5##
• n 0, 1, or 2
• each R 1 , R 2 , and R 3 are independently halogen, hydrogen, --NO 2 , --NH 2 , --NH(C 1 -C 6 alkyl), --N(C 1 -C 6 alkyl) 2 , --CN, --CF 3 , --C 1 -C 6 alkyl, --C 1 -C 6 alkoxy, --CO 2 H, or --CO 2 C 1 -C 6 alkyl; ##STR6##
• n 1 to 6;
• l 1 to 6;
• each R 11 and R 12 are independently hydrogen, C 1 -C 6 alkyl, or benzyl; and R 13 is --OR 11 or --NHOR 11 .
• Q is D-alanine, D-valine, D-leucine, D-isoleucine, D-phenylalanine, D-proline, D-serine, D-threonine, D-tyrosine, D-asparagine, D-glutamine, D-lysine, D-arginine, D-tryptophan, D-histidine, D-cysteine, D-methionine, D-aspartic acid, D-glutamic acid, or D-homophenylalanine.
• Q is L-alanine, L-valine, L-leucine, L-isoleucine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tyrosine, L-asparagine, L-glutamine, L-lysine, L-arginine, L-tryptophan, L-histidine, L-cysteine, L-methionine, L-aspartic acid, L-glutamic acid, or L-homophenylalanine.
• the present invention provides the compounds:
• Also provided is a method of treating atherosclerotic plaque rupture comprising administering to a patient having an atherosclerotic plaque at risk for rupture a therapeutically effective amount of a compound of Formula I.
• Also provided is a method of treating tumor angiogenesis comprising administering to a patient having tumor angiogenesis a therapeutically effective amount of a compound of Formula I.
• the arthritis is rheumatoid arthritis.
• the arthritis is osteoarthritis.
• Also provided is a method of treating autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes comprising administering to a patient having autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes a therapeutically effective amount of a compound of Formula I.
• the group ##STR12## is located at the 2- or 3-position.
• alkoxy means an alkyl group attached to an oxygen atom.
• Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.
• halogen includes chlorine, fluorine, bromine, and iodine.
• aryl means an aromatic hydrocarbon. Representative examples of aryl groups include phenyl and naphthyl.
• phenyl also includes substituted phenyl wherein one or more hydrogen atom on the phenyl ring is replaced with an organic radical.
• suitable substituents include, but are not limited to, halogen, C 1 -C 6 alkoxy, --CF 3 , --NO 2 , --CN, --NH 2 , --NH(C 1 -C 6 alkyl), or --N(C 1 -C 6 alkyl) 2 .
• heteroaryl means an aryl group wherein one or more carbon atom of the aromatic hydrocarbon has been replaced with a heteroatom.
• heteroaryl groups include, but are not limited to, 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl.
• alkyl means a straight or branched chain hydrocarbon. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl.
• alkene means a straight or branched hydrocarbon having one or more carbon-carbon double bond.
• cycloalkyl means a cyclic hydrocarbon.
• examples of cycloalkyl groups include cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cyclooctane.
• heteroatom includes oxygen, nitrogen, and sulfur.
• the aryl or heteroaryl groups may be substituted with one or more substituents, which can be the same or different.
• substituents include alkyl, alkoxy, thioalkoxy, hydroxy, halogen, trifluoromethyl, amino, alkylamino, dialkylamino, --NO 2 , --CN, --CO 2 H, --CO 2 alkyl, --SO 3 H, --CHO, --CO alkyl, --CONH 2 , --CONH-alkyl, --CONHR q , --CON(alkyl) 2 , --(CH 2 ) n --NH 2 , where n is 1 to 5 and --(CH 2 ) n --NH-alkyl, --NHR q , or --NHCOR q , and R q is hydrogen or alkyl.
• the group ##STR14## is attached at the 2- or 3-position of the tricyclic ring system as follows: ##STR15##
• the compounds of Formula I can be administered to a patient either alone or as part of a pharmaceutically acceptable composition.
• the compositions can be administered to patients such as humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
• compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
• suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
• Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
• compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
• adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
• Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
• isotonic agents for example sugars, sodium chloride, and the like.
• Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
• fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid
• binders as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose and acacia
• humectants as for example, glycerol
• disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate
• solution retarders as for example paraffin
• absorption accelerators as for example, quaternary ammonium compounds
• wetting agents as
• compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
• Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
• inert diluents commonly used in the art, such as water or other solvents, solubilizing
• composition can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
• suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
• compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
• suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
• Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.
• the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required.
• Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
• the compounds of the present invention can typically be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day.
• dosage levels in the range of about 0.1 to about 1,000 mg per day.
• a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is preferable.
• the specific dosage used can vary.
• the dosage can depended on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well-known to those skilled in the art.
• the term "patient" includes humans and animals.
• salts refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
• salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention.
• salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
• Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts, and the like.
• alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like
• nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. See, for example, Berge S. M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19 which is incorporated herein by reference.
• esters of the compounds of this invention include C 1 -C 6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C 5 -C 7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to, benzyl. C 1 -C 4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
• Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C 1 -C 6 alkyl amines and secondary C 1 -C 6 dialkyl amines wherein the alkyl groups are straight or branched chain.
• the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom.
• Amides derived from ammonia, C 1 -C 3 alkyl primary amines and C 1 -C 2 dialkyl secondary amines are preferred.
• Amides of the compounds of the invention may be prepared according to conventional methods.
• prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
• a thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
• the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
• the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
• the compounds of the present invention can exist in different stereoisometric forms by virtue of the presence of asymmetric centers in the compounds. It is contemplated that all stereoisometric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of this invention.
• the compounds of the present invention can be made using standard organic chemistry, such as through organic synthesis or using combinatorial chemistry.
• the compounds of the present invention can be made through metabolism. It is intended that the invention encompass the compounds made in any manner.
• the compounds of the present invention are administered to a patient in need of matrix metalloproteinase inhibition.
• patients in need of matrix metalloproteinase inhibition are those patients having a disease or condition in which a matrix metalloproteinase plays a role.
• diseases include, but are not limited to, multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurysm, heart failure, periodontal disease, corneal ulceration, burns, decubital ulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, osteoporosis, rheumatoid or osteoarthritis, renal disease, left ventricular dilatation, or other autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes.
• a “therapeutically effective amount” is an amount of a compound of Formula I that when administered to a patient having a disease that can be treated with a compound of Formula I ameliorates a symptom of the disease.
• a therapeutically effective amount of a compound of Formula I is readily determined by one skilled in the art by administering a compound of Formula I to a patient and observing the results.
• the compounds of the present invention can be obtained using the general synthetic procedure outlined in Scheme 1.
• the requisite sulfonyl chlorides (1) are readily synthesis by those skilled in the art by direct chlorosulfonation of the parent ring system, or chemical conversion of a substituent on the ring into the sulfonyl chloride (such as the conversion of an amine to a sulfonyl chloride [Meerwein, et al; Chem. Ber., 1957;90:841, which is hereby incorporated by reference]).
• the sulfonyl chloride (1) is then condensed with an amino acid compound (2) employing a base catalyst such as triethylamine or N-methylmorpholine in a solvent such as dichloromethane or tetrahydrofuran at ambient temperature. If the amino acid compound (2) is protected as a carboxylic ester, it can be easily hydrolyzed to the corresponding carboxylic acid (3) of the present invention.
• a base catalyst such as triethylamine or N-methylmorpholine
• a solvent such as dichloromethane or tetrahydrofuran
• the acid (3) may also be converted to the hydroxamic acid (4) of the present invention by coupling (using standard methods such as an acid halide, a mixed anhydride, or a carbodiimide) with hydroxyl amine (or a suitably O-protected analog which must then be deprotected to give the hydroxamic acid (4)).
• standard methods such as an acid halide, a mixed anhydride, or a carbodiimide
• the crude thianthrene-2-sulfonyl chloride (1.19 g, 3.77 mmol) was mixed with 0.79 g (3.77 mmol) of (L)-valine-t-butyl ester and triethyl amine (1.58 mL, 11.3 mmol) in 50 mL of dichloromethane. After 2 hours, the reaction was partitioned between 1 M HCl and dichloromethane. The organic phase was washed with saturated sodium carbonate solution, dried over magnesium sulfate, and concentrated to give an oily green solid. This compound (0.46 g, 1.0 mmol) was stirred in 5 mL of trifluoroacetic acid for 1 hour and then concentrated in vacuo. The residue was triturated with diethyl ether to give 0.26 g of the title compound as a fluffy white solid.
• Step (a) When in the procedure of Example 1, Step (a), thianthrene is replaced with phenoxathiin, phenoxathiine-2-sulfonyl chloride is obtained as a yellow solid which is used without further purification.
• the phenoxathiine-2-sulfonyl chloride (0.75 g, 2.52 mmol) was mixed with (L)-homo-phenylalanine (0.448 g, 2.52 mmol) and triethylamine (1.2 mL, 7.56 mmol) in 50 mL of water and 50 mL of tetrahydrofuran. The resulting mixture was stirred for 2 hours and then concentrated in vacuo. The residue was partitioned between 1 M HCl and ethyl acetate. The organic phase was dried over magnesium sulfate, and concentrated to give an oily solid. Trituration with diethyl ether gave (S)-2-(phenoxathiine-2-sulfonylamino)-4-phenyl-butyric acid as an off-white powder; mp 149-154° C.
• Step (a) When in the procedure of Example 1, Step (a), thianthrene is replaced with xanthene, 9H-xanthene-2-sulfonyl chloride is obtained as a pale pink solid which is used without further purification.
• Step (b) phenoxathiine-2-sulfonyl chloride is replaced with 9H-xanthene-2-sulfonyl chloride, (S)-4-phenyl-2-(9H-xanthene-2-sulfonylamino)-butyric acid is obtained as a white solid;
• Step (b) When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride, (S)-3-methyl-2-(phenoxathiine-2-sulfonylamino)-butyric acid is obtained as an off-white solid;
• Step (b) When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (D)-valine-t-butyl ester, (S)-3-methyl-2-(phenoxathiine-2-sulfonylamino)-butyric acid is obtained as an off-white solid; mp 171-175° C.
• Step (b) When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-alanine-t-butyl ester, (S)-2-(phenoxathiine-2-sulfonylamino)-propionic acid is obtained as a white solid; mp 75-85° C.
• Step (b) When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-methionine-t-butyl ester, (S)-4-methanesulfinyl-2-(phenoxathiine-2-sulfonylamino)-butyric acid is obtained as a white solid;
• Step (b) When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-leucine-t-butyl ester, (S)-4-methyl-2-(phenoxathiine-2-sulfonylamino)-pentanoic acid is obtained; mp 120-130° C.
• Step (b) When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-phenylalanine-t-butyl ester, (S)-2-(phenoxanthiine-2-sulfonylamino)-3-phenyl-propionic acid is obtained; mp 120-130° C.
• Step (b) When in the procedure of Example 2, Step (b), (L)-homo-phenylalanine is replaced with (L)-S-trityl cysteine, (R)-2-(phenoxathiine-2-sulfonylamino)-3-tritylsulfanyl-propionic acid is obtained.
• Step (b) When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-O-t-butyltyrosine-t-butyl ester, (S)-3-(4-hydroxy-phenyl)-2-(phenoxathiine-2-sulfonylamino)-propionic acid is obtained;
• Step (b) When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-tryptophan-t-butyl ester, (S)-3-(1H-indol-3-yl)-2-(phenoxathiine-2-sulfonylamino)-propionic acid is obtained; mp 120-130° C.
• Step (b) When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-asparagine-t-butyl ester, (S)-2-(phenoxathiine-2-sulfonylamino)-succinamic acid is obtained; mp 165-175° C.
• Step (b) When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-phenylglycine-t-butyl ester, (S)-2-(phenoxathiine-2-sulfonylamino)-phenyl acid is obtained; mp 175-185° C.
• MMP-1, MMP-7, and MMP-13 activity was assayed in a method similar to MMP-2 and MMP-3 (SCD and GCD).
• MMP-1 can be obtained from Washington University School of Medicine, St. Louis, Mo.
• MMP-7 can be obtained in accordance with the known procedure set forth by Ye Q. Z., Johnson L. L., and Baragi V., "Gene Syntheses and Expression in E. coli for PUMP, a Human Matrix Metalloproteinase,” Biochem. and Biophys. Res.
• MMP13 can be obtained in accordance with the known procedure set forth by Freije J. M. P. et al., "Molecular Cloning and Expression of Collegenase-3, a Novel Human Matrix Metalloproteinase Produced by Breast Carcinomas," J. Bio. Chem., 1994;269:16766-16773.
• Activated full-length enzymes are assayed at 5 nM, Stromelysin Catalytic Domain (SCD) at 10 nM, and Gelatinase A Catalytic Domain (GaCD) at 1 nM. Inhibitors are screened from 100 ⁇ M to 1 nM.
• Full-length enzymes (MMP-1 and MMP-7) are assayed in 50 mM HEPES, 10 mM CaCl 2 , pH 7.0; SCD in 50 mM MES, 10 mM CaCl 2 , pH 6.0; and GaCD in 50 mM MOPS, 10 mM CaCl 2 , 10 ⁇ M ZnCl 2 , pH 7.0. The change in absorbance at 405 nM is monitored on a ThermoMax microplate reader at room temperature continuously for 20 minutes.
• Pro is proline
• Leu is leucine
• Gly is glycine
• Et is ethyl
• HEPES is 4-(2-hydroxymethyl)-piperazine-1-ethane sulfonic acid
• MES is 2-morpholinoethane sulfonic acid monohydrate
• MOPS is 3-morpholtriopropane sulfonic acid.

Abstract

Description

                                  TABLE 1                                 
__________________________________________________________________________
IC.sub.50 (μM)                                                         
Example                                                                   
     MMP-1                                                                
         MMP-2CD                                                          
               MMP-3CD                                                    
                     MMP-7                                                
                         MMP-9                                            
                             MMP-13CD                                     
                                   MMP-14CD                               
__________________________________________________________________________
1    >100                                                                 
         15.4  6.9   27.6                                                 
                         >100                                             
                             >100  40                                     
  2 >100 0.033 0.054 7.9 16.63 1.39 0.092                                 
  3 >100 0.2 0.068 3.2 >100 0.5 1                                         
  4 39 0.0335 0.053 6.7 19 4.1 0.28                                       
  5 >100 0.069 0.18 23 82 1.8 0.39                                        
  6 >100 0.65 0.44 34 >100 4.3 4.1                                        
  7 >100 2.3 3.75 24 >100 73 3.7                                          
  8 6.25 0.027 0.0155 19 12 0.27 0.155                                    
  9 76 0.033 0.295 19 23 5.25 0.19                                        
  10  72 0.0585 0.165 9.15 38 4.1 0.285                                   
  11  55 0.0235 0.0625 8.7 18 3.9 0.3                                     
  12  >100 0.17 0.35 91 >100 8.7 0.5                                      
  13  >100 3.2 4.65 66 >100 36 7.4                                        
  14  87 0.09 0.12 17 18 2.3 0.2                                          
  15  >100 0.91 0.86 54 >100 16 3.8                                       
  16  >100 0.1133 0.41 14 53 4.4 1.55                                     
  17  >100 0.15 2 >100 >100 12 0.94                                       
__________________________________________________________________________

Claims (28)

Priority Applications (1)

Applications Claiming Priority (2)

Related Parent Applications (1)

Related Child Applications (1)

Publications (1)

Family

ID=26790112

Family Applications (1)

Country Status (1)

Cited By (24)

Citations (3)

• 1999
  • 1999-07-26 US US09/361,077 patent/US6117869A/en not_active Expired - Fee Related

Patent Citations (3)

Non-Patent Citations (76)

Similar Documents

Legal Events